Efficacy and safety of GLP-1 receptor agonists in patients with schizophrenia spectrum disorders treated with antipsychotics: a systematic review and meta-analysis

Weight gain and impaired glucose metabolism are common complications of antipsychotic treatment in schizophrenia spectrum disorders (SSD). While beneficial in other populations, the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in SSD remain unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating GLP-1 RAs versus placebo in SSD patients treated with antipsychotics. PubMed, Scopus, and Web of Science were searched until January 2026. Random-effects models were used to pool mean differences (MDs), standardized mean differences (SMDs), and risk ratios (RRs), as appropriate. Seven RCTs including 481 participants were included. Compared with placebo, GLP-1 RAs significantly reduced body weight (MD -6.98 kg; 95% CI -10.53 to -3.43), BMI (MD -2.51 kg/m²; 95% CI -3.51 to -1.51), waist circumference (MD -5.05 cm; 95% CI -6.66 to -3.44), HbA1c (MD -0.32 percentage points; 95% CI -0.38 to -0.26), and fasting blood glucose (MD -0.54 mmol/L; 95% CI -0.83 to -0.25). Heterogeneity was substantial for body weight (I²=93%) and BMI (I²=80%). No significant effects emerged for blood pressure or lipid parameters. Psychiatric symptom severity did not differ between GLP-1 RAs and placebo (SMD -0.05; 95% CI -0.36 to 0.25). Gastrointestinal adverse events were more frequent with GLP-1 RAs than with placebo, while overall study drop-out did not differ between groups. GLP-1 RAs improve short-term anthropometric and glycemic outcomes in SSD patients treated with antipsychotics. However, the limited number of trials, substantial heterogeneity in weight-related outcomes, and relatively short follow-up warrant cautious interpretation and further large-scale RCTs.